Cyclic peptide CXCR4 antagonists

Abstract

Provided are lactam-cyclized peptide CXCR4 antagonists useful in the treatment of cancers, rheumatoid arthritis, pulmonary fibrosis, and HIV infection.

1. A lactam-cyclized peptide of formula I: 
       
         
           
                 
               
                   (SEQ ID NO: 1) 
                 
                 
                 
               
                   R 1 -cyclo[X 1 -Tyr-X 3 -DArg-2Nal-Gly-X 7 ]-X 8 -X 9 -X 10 -R 2   
                   (I) 
                 
             
                
               
            
             
                
               
            
           
         
         wherein:
 a) said lactam is formed by an amide bond between the side chain amino group of X 1  and the side chain carboxyl group of X 7 , wherein X 1  and X 7  are, respectively, a pair selected from the group consisting of ( D/L )Agl/Glu, Dab/Glu, and Dap/Glu, and R 1  is Ac or n-hexanoyl; or 
 b) said lactam is formed by an amide bond between the side chain carboxyl group of X 1  and the side chain amino group of X 7 , wherein X 1  and X 7  are, respectively, a pair selected from the group consisting of Asp/( D/L )Agl, Asp/Dab, Asp/Dap, Glu/( D/L )Agl, Glu/Dab, Glu/Dap, Glu/ D Dap, and Glu/Lys, and R 1  is Ac or Bz, or wherein X 1  and X 7  are, respectively, a pair selected from the group consisting of succinyl/( D/L )Agl, succinyl/Dab, succinyl/Dap, succinyl/Lys, and succinyl/Orn, and R 1  is absent; or 
 c) said lactam is formed by an amide bond between the α-amino group of X 1  and the side chain carboxyl group of X 7 , wherein X 1  and X 7  are, respectively, a pair selected from the group consisting of Ala/Glu, Ala/ D Glu,  D Ala/Glu,  D Ala/ D Glu, Dap(Ac)/Glu, Gly/Asp, Gly/Glu, Gly/ D Glu, Leu/Glu, Leu/ D Glu, Lys/ D Glu, Lys(Ac)/Glu, 2Nal/Glu, Phe/Glu, Phe/ D Glu,  D Phe/Glu, and  D Phe/ D Glu, and R 1  is absent; or 
 d) said lactam is formed by an amide bond between a non-α, non-side-chain amino group of X 1  and the side chain carboxyl group of X 7 , wherein X 1  and X 7  are, respectively, a pair selected from the group consisting of β-Ala/Asp, β-Ala/Glu, 5-amino-valeryl/Asp, 5-aminovaleryl/Glu, 4-AMB/Glu, 4-AMPA/Asp, and 4-AMPA/Glu, and R 1  is absent; or 
 e) said lactam is formed by an amide bond between the α-amino group of X 2  and the side chain carboxyl group of X 7 , wherein X 2  and X 7  are, respectively, a pair selected from the group consisting of Tyr/Asp, Tyr/Glu, and Tyr/ D Glu, and R 1  and X 1  are each absent; 
 R 1  is a substituent on the α-amino group of X 1  when X 1  contains an α-amino group and said α-amino group is not a constituent of said lactam amide bond, selected from the group consisting of Ac, Bz, and n-hexanoyl, or is absent, wherein X 1  is selected from the group consisting of ( D/L )Agl, Asp, Dab, Dap, and Glu; 
 X 1  is selected from the group consisting of ( D/L )Agl, Ala, β-Ala,  D Ala, 5-aminovaleryl, 4-AMB, 4-AMPA, Asp, Dab, Dap, Dap(Ac), Glu, Gly, Leu, Lys, Lys(Ac), 2Nal, Phe,  D Phe, and succinyl, or is absent; 
 X 3  is selected from the group consisting of Arg, Lys, Lys(iPr), and Lys(Me 2 ); 
 X 7  is selected from the group consisting of ( D/L )Agl, Asp, Dab, Dap,  D Dap, Glu,  D Glu, Lys, and Orn; 
 X 8  is selected from the group consisting of β-Ala, Arg,  D Arg, Gly, Lys, Lys(iPr), and Orn, or is absent; 
 X 9  is selected from the group consisting of Gly, 2Nal,  D 2Nal, and  D Phe, or is absent; 
 X 10  is 2Nal, or is absent; 
 
         wherein when X 8  is absent, X 9  and X 10  are each absent, and when X 9  is absent, X 10  is absent, and
 R 2  is selected from the group consisting of NH 2  and NHEt, or 
 a pharmaceutically acceptable salt thereof. 
 
       
     
     
       2. The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 , wherein:
 R 1  is selected from the group consisting of Ac and Bz, or is absent; 
 X 1  is selected from the group consisting of β-Ala, 4-AMB, 4-AMPA, Asp, Dab, Dap, Dap(Ac), Glu, 2Nal, Phe, and succinyl, or is absent; 
 X 3  is selected from the group consisting of Arg, Lys, Lys(iPr), and Lys(Me 2 ); 
 X 7  is selected from the group consisting of Asp, Dab, Dap, Glu,  D Glu, Lys, and Orn; 
 X 8  is selected from the group consisting of Arg and Lys, or is absent; 
 X 9  is absent; 
 X 10  is absent; and 
 R 2  is selected from the group consisting of NH 2  and NHEt. 
 
     
     
       3. The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 , wherein:
 R 1  is selected from the group consisting of Ac and Bz, or is absent; 
 X 1  is selected from the group consisting of  D Ala, 5-aminovaleryl, 4-AMPA, Asp, Glu, Leu, Lys(Ac), Phe,  D Phe, and succinyl; 
 X 3  is selected from the group consisting of Arg, Lys, Lys(iPr), and Lys(Me 2 ); 
 X 7  is selected from the group consisting of ( D/L )Agl, Asp, Dab, Dap,  D Dap, Glu, and  D Glu; 
 X 8  is selected from the group consisting of Arg,  D Arg, and Lys, or is absent; 
 X 9  is absent; 
 X 10  is absent; and 
 R 2  is selected from the group consisting of NH 2  and NHEt. 
 
     
     
       4. The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 , wherein:
 R 1  is selected from the group consisting of Ac, Bz, and n-hexanoyl, or is absent; 
 X 1  is selected from the group consisting of ( D/L )Agl, Ala, β-Ala, Asp, Dap, Glu, Gly, Lys, and Phe; 
 X 3  is selected from the group consisting of Arg, Lys, Lys(iPr), and Lys(Me 2 ); 
 X 7  is selected from the group consisting of ( D/L )Agl, Asp, Dap, Glu, and  D Glu; 
 X 8  is selected from the group consisting of β-Ala, Arg, Gly, Lys, Lys(iPr), and Orn, or is absent; 
 X 9  is selected from the group consisting of Gly, 2Nal,  D 2Nal, and  D Phe, or is absent; 
 X 10  is 2Nal, or is absent; and 
 R 2  is selected from the group consisting of NH 2  and NHEt. 
 
     
     
       5. The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 , wherein:
 R 1  is selected from the group consisting of Ac and Bz, or is absent; 
 X 1  is selected from the group consisting of Ala, 5-aminovaleryl, Asp, Glu, Gly, Phe,  D Phe, and succinyl; 
 X 3  is selected from the group consisting of Arg, Lys(iPr), and Lys(Me 2 ); 
 X 7  is selected from the group consisting of ( D/L )Agl, Asp, Dap, Glu, and  D Glu; 
 X 8  is selected from the group consisting of β-Ala, Arg, Gly, Lys, Lys(iPr), and Orn, or is absent; 
 X 9  is selected from the group consisting of Gly,  D 2Nal, and  D Phe, or is absent; 
 X 10  is 2Nal, or is absent; and 
 R 2  is selected from the group consisting of NH 2  and NHEt. 
 
     
     
       6. The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 , wherein:
 X 1  is selected from the group consisting of Gly and Phe; 
 X 3  is Lys(iPr); and 
 X 7  is  D Glu. 
 
     
     
       7. The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 5 , wherein:
 R 1  is absent; 
 X 1  is selected from the group consisting of Gly and Phe; 
 X 3  is Lys(iPr); 
 X 7  is  D Glu; 
 X 8  is selected from the group consisting of Arg and Lys(iPr), or is absent; 
 X 9  is absent; 
 X 10  is absent; and 
 R 2  is selected from the group consisting of NH 2  and NHEt. 
 
     
     
       8. A lactam-cyclized peptide of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       9. The lactam-cyclized peptide of  claim 8 , wherein said pharmaceutically acceptable salt is an acetic acid salt. 
     
     
       10. A pharmaceutical composition, comprising a lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
       11. A pharmaceutical composition, comprising said acetic acid salt of said lactam-cyclized peptide of  claim 9 , and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
       12. A method of treating rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia, comprising administering to a patient in need thereof an effective amount of a lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
       13. A method of treating rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia, comprising administering to a patient in need thereof an effective amount of said lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 8 . 
     
     
       14. The method of  claim 13 , wherein said pharmaceutically acceptable salt of said lactam-cyclized peptide is an acetic acid salt.